阅读说明：本技术 松香烷型二萜类化合物在制备预防和/或治疗血栓性疾病的药物中的应用 (Application of abietane diterpenoid compound in preparation of medicine for preventing and/or treating thrombotic diseases ) 是由 许刚 赵金华 夏凡 林丽莎 于 2019-11-14 设计创作，主要内容包括：本发明提供了松香烷型二萜类化合物在制备预防和/或治疗血栓性疾病的药物中的应用,属于药物技术领域。本发明涉及的松香烷型二萜类化合物对花生四烯酸诱导的兔血小板聚集具有显著的抑制活性,且具有显著的体内抗血栓活性,以所述松香烷型二萜类化合物为活性成分制备预防和/或治疗血栓性疾病药物,具有潜在临床应用价值。(The invention provides an application of abietane diterpenoid compounds in preparation of medicines for preventing and/or treating thrombotic diseases, belonging to the technical field of medicines. The abietane diterpenoid compound has obvious inhibitory activity on rabbit platelet aggregation induced by arachidonic acid and obvious in-vivo antithrombotic activity, and has potential clinical application value when being used as an active ingredient to prepare medicines for preventing and/or treating thrombotic diseases.)

1. The application of the abietane diterpenoid compounds in the preparation of the medicines for preventing and/or treating thrombotic diseases is characterized in that the abietane diterpenoid compounds are one or more of the compounds with the structures shown in the formulas 1-11:

2. the use according to claim 1, wherein the medicament for preventing and/or treating thrombotic diseases consists of abietane-type diterpenoid compounds and pharmaceutically acceptable excipients.

3. The use according to claim 2, wherein the pharmaceutically acceptable excipients comprise one or more of pharmaceutical carriers, surfactants, buffer substances, disintegrants, binders, fillers, lubricants, excipients, solubilizers, flavoring agents and coloring agents.

4. The use according to claim 2 or 3, wherein the abietane-type diterpenoid compound is contained in the medicament for the prevention and/or treatment of thrombotic diseases in an amount of 0.05 to 99 wt.%.

5. The use according to claim 4, wherein the abietane-type diterpenoid compound is contained in the medicament for the prevention and/or treatment of thrombotic diseases in an amount of 0.5 to 90 wt.%.

6. The use of claim 1, wherein the dosage form of the medicament for preventing and/or treating thrombotic diseases comprises tablets, capsules, granules, pills, oral liquid preparations, injections or freeze-dried powder injections.

7. The use according to claim 1, wherein the thrombotic disease comprises one or more of coronary heart disease, ischemic cerebrovascular disease and peripheral vascular disease.

8. The use according to claim 7, wherein the coronary heart disease comprises angina pectoris and/or myocardial infarction; the ischemic cerebrovascular disease comprises stroke and/or cerebral infarction; the peripheral vascular disease includes atherosclerotic thrombotic disease.

Technical Field

The invention relates to the technical field of medicines, in particular to application of abietane diterpenoid compounds in preparing medicines for preventing and/or treating thrombotic diseases.

Background

The sage (Salvia) plant is one of the famous medicinal plant groups, and has 82 kinds in China, wherein the transected mountain area is one of three global distribution centers, and the resource is extremely rich. Besides the salvia miltiorrhiza (s.militiorhiza) listed as the top grade in the book of shennong's herbal, more than 20 plants of the genus, such as Yunnan salvia, salvia miltiorrhiza, etc., are used as medicines in various folks, and have the efficacies of promoting blood circulation, removing blood stasis, cooling blood, stopping bleeding, etc. The sage plants mainly contain diterpenoid components and polyphenol components, wherein the diterpenoid components have changeable structures and obvious activities, and are always hot points of international research. However, in recent years, the research on the pharmacological activity of diterpene components in salvia plants mainly focuses on the fields of anti-tumor and anti-bacterial.

The arachidonic acid metabolic pathway is an important amplification mechanism of the platelet activation process, and the metabolite thromboxane A₂(TXA₂) Is a strong inducer of platelet aggregation. TXA₂Acting on platelet thromboxane receptors can promote the activation and aggregation thereof, acting on endothelial thromboxane receptors can promote the expression of adhesion molecules, acting on vascular smooth muscle cells can increase vascular tone, and the like (Giannarelli C, Zafar MU and Badimon JJ.Prostanoid and TP-receptors: is thermal a roll for the same anti-inflammatory agent. TXA has been found to be involved in the pathological process of various thrombotic diseases, such as myocardial infarction, unstable angina and atherosclerosis₂Is up-regulated, and TXA₂Mediated platelet aggregation plays an important role in the pathophysiological processes of thrombosis (CreScent M, Menke L, Chan MV, Armstrong PC and Warner TD. Eicosanoids in platelets and the effect of the injection by aspirinin into the cardiovascular system (and beyond). Br J Pharmacol., 2019; 176, 988-. Therefore, the arachidonic acid metabolic pathway is an important link in the platelet aggregation process, and the arachidonic acid metabolic pathway is also an important link in the platelet aggregation processIs an important target for the development of anti-platelet antithrombotic drugs (Coccheri S. antiplatelet drugs-do we connected new options.

At present, the clinical anti-platelet antithrombotic drugs mainly comprise COX-1 inhibitors (such as aspirin), GPIIbIIIa receptor antagonists (such as tirofiban) and P2Y₁₂Receptor antagonists (e.g., clopidogrel and prasugrel) of the three classes (FanP, Gao Y, Zheng M, T X, Schoenhagen P and Jin Z. Recent progress and market analysis of antimicrobial drugs. J Thorac Dis., 2018; 10, 2011-. Due to the large individual difference in the curative effect of the drugs and the bleeding tendency at high dose, the existing anti-platelet antithrombotic drugs have the defect of narrow safety window and may generate drug resistance (McFadyen JD, Schaff M and Peter K.Current and functional anti-platelet therapeutics: medicine on prediction of thrombosis. Nat RevCardiol.2018; 15, 181-. For example, the use of aspirin has not been able to completely avoid ischemic events, it has a poor thrombus-inhibiting effect in an inflammatory state where COX-2 is abundantly expressed, and side effects such as aspirin resistance, allergy, and gastrointestinal bleeding may occur with the use of the drug. Thienopyridines P2Y₁₂Receptor antagonists such as clopidogrel and prasugrel need to be metabolized in vivo to produce active molecules, which have large individual differences in pharmacokinetics and pharmacodynamics and may cause high reactivity of therapeutic platelets. Therefore, the search for effective antithrombotic drugs against thrombosis with low risk of bleeding is still urgent.

Disclosure of Invention

The invention aims to provide application of abietane diterpenoid compounds in preparation of medicines for preventing and/or treating thrombotic diseases.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides an application of abietane diterpenoid compounds in preparation of medicines for preventing and/or treating thrombotic diseases, wherein the abietane diterpenoid compounds are one or more of compounds with structures shown in formulas 1-11:

preferably, the medicament for preventing and/or treating thrombotic diseases consists of abietane diterpenoid compounds and pharmaceutically acceptable auxiliary materials.

Preferably, the pharmaceutically acceptable auxiliary materials comprise one or more of a drug carrier, a surfactant, a buffer substance, a disintegrating agent, a binder, a filler, a lubricant, an excipient, a solubilizer, a flavoring agent and a coloring agent.

Preferably, the content of the abietane-type diterpenoid compound in the medicament for preventing and/or treating the thrombotic diseases is 0.05-99 wt.%.

Preferably, the content of the abietane-type diterpenoid compound in the medicament for preventing and/or treating the thrombotic diseases is 0.5-90 wt.%.

Preferably, the dosage form of the medicament for preventing and/or treating thrombotic diseases comprises tablets, capsules, granules, pills, oral liquid preparations, injections or freeze-dried powder injections.

Preferably, the thrombotic disease comprises one or more of coronary heart disease, ischemic cerebrovascular disease and peripheral vascular disease.

Preferably, the coronary heart disease comprises angina pectoris and/or myocardial infarction; the ischemic cerebrovascular disease comprises stroke and/or cerebral infarction; the peripheral vascular disease includes atherosclerotic thrombotic disease.

The invention provides an application of abietane diterpenoid compounds in preparation of medicines for preventing and/or treating thrombotic diseases, wherein the abietane diterpenoid compounds are one or more of compounds with structures shown in formulas 1-11. The abietane diterpenoid compound has obvious inhibitory activity on rabbit platelet aggregation induced by Arachidonic Acid (AA) and obvious in-vivo antithrombotic activity, and has potential clinical application value when being used as an active ingredient to prepare medicines for preventing and/or treating thrombotic diseases.

Drawings

FIG. 1 is a carbon spectrum (150MHz, acetone-d) of Compound 2₆)；

FIG. 2 is a mass spectrum of Compound 2;

FIG. 3 is a graph showing the effect of Compound 8 on the aggregation rate of arachidonic acid-induced rabbit platelet aggregation at various concentrations;

FIG. 4 is a graph of the effect of compounds 2, 6, 4, 7 and aspirin on the aggregation rate of arachidonic acid-induced rabbit platelet aggregation;

FIG. 5 is a graph of concentration-dependent inhibition of arachidonic acid-induced rabbit washed platelet aggregation by the compound of example 1 and aspirin;

FIG. 6 shows different pairs of compounds to FeCl₃Graph of the effect of the time to occlusion of the carotid artery in rats after induced injury.

Detailed Description

The invention provides an application of abietane diterpenoid compounds in preparation of medicines for preventing and/or treating thrombotic diseases, wherein the abietane diterpenoid compounds are one or more of compounds with structures shown in formulas 1-11:

in the invention, the abietane diterpenoid compound has obvious antiplatelet activity and in-vivo antithrombotic activity, and the medicine for preventing and/or treating thrombotic diseases prepared by using the abietane diterpenoid compound as an active ingredient has potential clinical application value. The specific source of the abietane diterpenoid compound is not particularly limited, and the abietane diterpenoid compound can be obtained by separation from plants (such as Salvia prattii (s.prattii)) or by chemical synthesis. In the present invention, the english names and acronyms of the structural compounds represented by formulas 1 to 11 are, in order:

14-Methoxyytaxodione (Compound 1);

montbretol (compound 2);

royleanone (compound 3);

1,2-anthracenedione,5,6,7, 8-tetrahydroo-5, 5, 9-trimethy-3- (1-methythynyl) (compound 4);

isotanshinone IIA (compound 5);

cryptoacetalide (compound 6);

7-methyl-3- (1-methythyyl) -8- (4-methyl-3-penten-1-yl) -2-naphthalenol (Compound 7);

1-oxoaethiopinone (compound 8);

viroxocin (compound 9);

salvilenone (compound 10);

phenaleno [1,9-bc ] furan-8(2H) -one,3-hydroxy-2,2,5-trimethyl-9- (1-methythynyl) (Compound 11).

The correspondence between the structure of the abietane diterpenoid compound and the abbreviation thereof is specifically shown as follows:

in the present invention, the agent for preventing and/or treating thrombotic diseases preferably consists of abietane-type diterpenoid compounds and pharmaceutically acceptable excipients.

The pharmaceutically acceptable auxiliary materials are not particularly limited, and specifically, the pharmaceutically acceptable auxiliary materials preferably include one or more of a drug carrier, a surfactant, a buffer substance, a disintegrating agent, a binder, a filler, a lubricant, an excipient, a solubilizer, a flavoring agent and a coloring agent. The invention has no special limitation on the specific types of the auxiliary materials, and the auxiliary materials can be selected according to actual needs.

In the present invention, the content of the abietane-type diterpenoid compound in the drug for preventing and/or treating thrombotic diseases is preferably 0.05 to 99 wt.%, more preferably 0.5 to 90 wt.%.

The dosage form of the medicament for preventing and/or treating the thrombotic diseases is not specially limited, and the medicament can be selected according to actual requirements, and specifically can be tablets, capsules, granules, pills, oral liquid preparations, injections or freeze-dried powder injections. The method for preparing the medicament in different dosage forms is not particularly limited, and the method known by the person skilled in the art can be adopted.

In the present invention, the dose administered by the agent for the prophylaxis and/or treatment of thrombotic disorders will vary with the compound used, the mode of administration, the desired treatment and the disorder indicated. For example, for oral administration, the daily dose of the abietane-type diterpenoid compound or a pharmaceutically acceptable salt thereof may range from 0.01 micrograms per kilogram body weight (μ g/kg) to 100 milligrams per kilogram body weight (mg/kg).

In the invention, the thrombotic diseases preferably comprise one or more of coronary heart disease, ischemic cerebrovascular disease and peripheral vascular disease; wherein the coronary heart disease preferably comprises angina pectoris and/or myocardial infarction; the ischemic cerebrovascular disease preferably comprises stroke and/or cerebral infarction; the peripheral vascular disease preferably comprises atherosclerotic thrombotic disease.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.